2alpha,3alpha-epithioandrostane derivatives and process for preparing them



United States Patent 3,519,715 2a,3a-EPITHIOANDROSTANE DERIVATIVES ANDPROCESS FOR PREPARING THEM Wataru Nagata, Nishinomiya-shi, FumikazuMukawa,

Minoo-shi, Taichiro Komeno, Osaka-shi, and Sadao Hayashi, Ashiya-shi,Japan, assignors t Shionogi & Co., Ltd., Osaka, Japan No Drawing. FiledApr. 22, 1968, Ser. No. 723,256 Claims priority, application GreatBritain, Apr. 26, 1967, 19,248/ 67 Int. Cl. C07c 173/00 US. Cl. 424-24116 Claims ABSTRACT OF THE DISCLOSURE204,3a-epithio-17-oxygenated-5a-androstane derivatives, substituted byan alkyl group at either positions 7%, 7B or 85- having enhanced ratioof anabolic and antiestrogenic/ androgenic activities, a process forpreparing them and pharmaceuticals containing the compounds of thepresent invention.

The present invention relates to a new class of 205,305-epithiosteroids, a process for their preparation and a pharmaceuticalcomposition thereof. More particularly, it relates to a class of2u,3u-epithioandrostane derivatives substituted by a lower alkyl groupat either positions 7 w, 7,8- or 8,8, represented by general formula:

wherein X represents an oxygen atom, a ketal group or ORII in which Rrepresents a hydrogen atom, an alkyl group containing at most 6 carbonatoms, an alkenyl group containing at most 6 carbon atoms, or an alkynylgroup containing at most 6 carbon atoms; R represents a hydrogen atom, ahydrocarboncarboxylic acyl group containing 1-13 carbon atoms, acycloalkyl group containing up to ten carbon atoms or a cycloalkyl groupsubstituted by a 1-l0wer alkoxy group, the total number of carbon atomsbeing or less, and the ripple mark (-w) designates that the methyl groupisin the 70:,7fi or 85 configuration.

Some of the specific examples of the compound of the present inventionrepresented by general Formula I include:201,3a-epithio-7a-methy1-5a-androstan-17-one, 2a,3a-epithio-78-methyl-5a-androstan-17-one,20,3a-epithio-7a-methyl-5u-androstan-1713-01,2a,3a-epithio-7fl-methyl-5u-androstan-17 8-01,2a,3a-epithio-7u,17a-dimethyl-5a-androstan-173-01,2a,3a-epithio-7fl,17a-dimethyl-5a-androstan-175-01,2a,3a-epithio-7u-methyl-17a-ethynyl-5a-androstan-176-01,2a,3a-epithio-7fl-methyl-17a-ethynyl-5a-androstan-175-01,2a,3a-epithio-7ra-methyl-17a-vinyl-5a-androstan-175-01, 20:,3a-epithio-73-methyl-17u-vinyl-5a-androstan-175-01,20,3a-epithio-7u-methyl-17a-(1-propnyl)-5a-androstan- 17 3-01,2a,3u-epithio-7fi-methyl-17oc-hexyl-5a-androstan-175-01,

3,519,715 Patented July 7, 19702a,3a-epithio-Sp-methyI-Su-andmstan-17-one,20:,3u-epithio-8fl-methyl-5u-androstan-175-01,2u,3m-epithio-8B,17a-dimethyl-5u-androstan-175-01,2u,3a-epithio-8B-methyl-17a-vinyl-5a-androstan-175-01,2a,3a-epithio-8fl-methyl-17a-propenyl-5a-androstan- 17,8-01,2a,3a-epithio-8fi-methyl-l7a-ethynyl-5u-androstan-17 6-01, and the likeor their aliphatic or aromatic hydrocarboncarboxylic acid esters ortheir 17-cycloa1kyl ether with or without 1-alkoxy group or theirdialkyl or alkyleneketal.

As for the examples of the alkyl groups represented by R containing atmost 6 carbon atoms, methyl, ethyl, propyl, isopropyl, l-methylpropyl,butyl, pentyl, 2-methylpentyl and hexyl group, etc., may be cited. Forthe alkenyl groups containing at most 6 carbon atoms represented by Rvinyl, l-propenyl, 2-propenyl, butenyl, hexenyl are examples thereof;for the alkynyl groups containing at most 6 carbon atoms, ethynyl,l-propynyl, 2-butynyl, 2- hexynyl, etc., are examples thereof; for thehydrocarboncarboxylic acyl groups containing at most 13 carbon atoms ofR, formyl, acetyl, propionyl, butyryl, valeryl, caproyl, enanthoyl,acryl, undecenoyl, trimethylacetyl, 3- trimethylpropionyl,triethylacetayl, caprylyl, cyclopropanecarbonyl, cyclobutanecarbonyl,cyclopentanecarbonyl, cyclohexanecarbonyl, cyclopentaneacetyl,cyclopentanepropionyl, cyclohexaneacetyl, cyclohexanepropionyl,cyclopentanepropionyl, phenylpropionyl, phenoxyacetyl, etc., areexamples thereof; for the cycloalkyl groups (R) containing up to 10carbon atoms with or without l-alkoxy residue, l-methoxycyclopentyl,l-ethoxycyclohexyl, l-propoxycyclohexyl, l-methoxycyclohexyl, 1-ethoxycyclopentyl, l-propoxycyclopentyl, l-butoxycyclohexyl, 1methoxycycloheptyl, 1 ethoxycycloheptyl, 1- ethoxy-4-methylcyclohexyl,tetrahydropyranyl, tetrahydrofuranyl groups and the like may be cited.

The present invention also provides the first process for the productionof the compounds represented by the general Formula I, which comprisesreacting a compound represented by the general formula:

wherein X and the ripple mark have the above significances and Yrepresents a hydroxyl group, a halogen atom, an hydrocarboncarboxylicacyloxy group at most 8 carbon atoms, an alkanesulfonyloxy groupcontaining at most 4 carbon atoms or an arylsulfonyloxy group containingat most 7 carbon atoms which may be substituted by inert group; Zrepresents a cyano group or a lower hydrocarbon carboxylic acyl groupcontaining at most 8 carbon atoms, including thio derivatives, e.g., alower hydrocarbonthiocarboxylic acyl group, with an organic or inorganicbase.

As for the alkanesulfonyloxy group of Y in the general Formula 11 above,methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy,butanesulfonyloxy groups, etc., are examples thereof; for thearylsulfonyloxy group, benzenesulfonyloxy, phenylmethanesulfonyloxy,p-bromobenzenesulfonyloxy groups etc., are examples thereof; for thelower hydrocarboncarboxylic acyl group of Z, acetyl, propionyl,thioacetyl, methoxythioformyl, ethoxythioformyl, cyclohexanecarbonyl,etc., are examples thereof; and for a halogen atom, chlorine, bromine,iodine, etc., can be cited.

3 Some of the specific examples of these starting materials representedby general Formula II include:2fi-hydroxy-3a-thiocyanato-7a-methyl-iu-androstan-17- one,2u-thiocyanato-3fi-hydroxy-7j3-methyl-5a-androstan-17- one, 3a-thiocyanato-7 a-methyI-S u-androstane-2,B-, 17 p-diol and its2-acylates, 2a-thiocyanato-7a-methyl-Sotandrostane-3p,17fi-diol and its3-sulfonates, 3a-acetylthio-7,8-methyl-Sa-andrOStane-Zfl,17B-diol andits 2-sulfonates, 3a-propionylthio-7B-methyl-Sa-androstane-Zfi,17B-diol,3a-thiocyanato-7a,l7a-dimethyl-5a-androstane-Zfi,17,3-

diol and its 2-sulfonates or 2-carboxylic acyl esters, 3a-acetylthio-h,17a-dimethyI-Sa-andrOStane-ZB,17 8-diol and its2-sulfonates, 2a-cyclohexylcarbonylthio-7B,l7a-dimethyl-5a-androstane-3B,17 8-diol and its 3-sulfonates,3a-thiocyanato-7a-methyl-17a-ethynyl-Sa-andmstane- 25,17,8-diol and itsZ-sulfonates, 3 a-acetylthio-7fl-methyl-17a-ethynyl-ia-androstane-2B,

17]3-di1 and its 2-sulfonates and 2-carboxylates,3a-thiocyanato-7a-methyl-17a-vinyl-Sa-andrOstane-ZB,

17fl-diol and its 2-acylates,2a-thiocyanato-7p-methyl-17a-vinyl-5u-androstane-3fi,

17,8-diol and its 3-sulfonates,3a-thiocyanato-7a-methyl-17a-(1'-propynyl)-5a-androstane-2,B,17fi-diol,3a-thiocyanato-17fi-methyl-17a-hexyl-5u-androstane-2p,

17,8-diol, ZB-hydroxy-3u-thiocyanato-8p-methyl-5a-androstan-17- one,3a-thiocyanato-8fl-methyI-Sa-androstane-ZB,17B-diol and its 2-sulfonatesand Z-carboxylates, 3a-acetylthio-8 8-methyl-5a-androstane-2 3,17B-dioland its 2-sulfonates, 3u-thiocyanato-88,17a-dimethyl-Sa-andrQstane-ZB,17,6-

diol, 3 a-acetylthio-8ot,17a-dimethyl-Sea-androStane-Zfl,17,3-di0l,3a-thiocyanato-8 8-methyl-17a-propenyl-5u-androstane- 33,17,8-diol,2a-acetylthio-8p-methyl-17a-ethynyl-5a-androstane-3 8,

17B-diol, 3a-acetylthio-8 3-methyl-l7a-ethynyl-5a-androstane-lfi,

17fi-diol, Za-acetyIthiO-SB-methyl-17wethynyl-Sa-androstane-Ei5,1713-dl01, 3a-acetylthio-8fi3-methyl-17a-ethynyl-5a-androstane-Zfl,

17fi-diol, and the like and their sulfonates and carboxylates of thehydroxyl group at position 2 or 3. When the compounds have a hydroxylgroup in the l7-position, the hydroxyl group may be acylated oretherized as exemplified in the explanation of the objective compoundrepresented by general Formula I. a compound represented by generalFormula II with an organic or inorganic base to obtain the objectivecompounds of the present invention.

The process of the present invention may be effected, for example, bythe procedure in which a compound II The process of the presentinvention comprises reacting is reacted with any basic reagent rangingfrom weak to strong base, examples of a weak base being triethylamine,alumina, sodium hydrogen carbonate, or potassium carbonate, and examplesof a strong base being potassium hydroxide or sodium hydroxide, ortetramethylammonium hydroxide, in an inert solvent such as methanol,ethanol, propanol, dioxane, benzene, toluene, petroleum ether ordiglyme. The reaction temperature depends on the properties of thestarting material and the basic reagent, although usually C. torefluxing temperature of the solvent is used. When the staring materialpossesses an acyloxy group at position 17, hydrolysis thereby possiblyoccurs. However, it can be recovered by subsequent acylation with asuitable acylating agent. When the product possesses a free hydroxylgroup at position 17, it may optionally be acylated or treated with anenol ether or a dialkylketal of an alicyclic ketone to givel-alkoxycycloalkyl ether, or with dihydropyran or dihydrofuran to givetetrahydropyranyl ether or tetrahydrofuranyl ether respectively, or withan acylating agent to give acylates as defined in the explanation of theproduct of this invention or with an oxidizing agent to obtain a 17-oxocompound. When the product has oxygen as the X substituent at position17, it may be treated with an organometalic compound to obtain the17,8-hydroxy-l7a-hydrocarbon compound. When the product has an acyloxy,ketal or ether group at position 17, it may be treated with an acid or abase to prepare the -01 product. When the product has an unsaturatedhydrocarbon group at position 17, Le. the alkenyl or alkynyl group, itmay be hydrogenated to obtain the product having the alkyl or alkenylgroup respectively at position 17 of the compound.

The product of the present invention is isolated and purified by aconventional manner such as dilution with insoluble solvent, filtration,extraction, washing, drying, evaporation, chromatography,recrystallization, absorption and the like.

The compounds provided by the present invention have valuablepharmacological activities. For example, they are useful agents forregulation of physiological functions as evidenced by theirantiestrogenic activity, antiuterotropic activity, uterotropic activity,estrogenic activity, implantation inhibition, myogenic activity orandrogenic activity, etc. For instance,2a,3a-epithio-7a-methyl-5ot-androstan- 175-01 shows equal antiestrogenicactivity, a half of myogenic activity and twenty percent of androgenicactivity when compared to the reference compound, 2a,3a-Cpithi0-5a-androstan-l7/3-ol. Hence, the ratio of myogenic/androgenic activityis improved up to 250%, and antiestrogenic/ androgenic activity isimproved up to 500%. Further, 2a,3a-epithio-88-methyl-5a-androstan-175-01 and its acetate show almost equalanti-estrogenic activity 16% of myogenic activity and 5% of androgenicactivity when compared to 2a,3a-epithio-5u-androstan-l7fl-ol, one of thebest known myogenic compounds. Hence, the ratio of myogenic/androgenicactivity is improved up to 320%. Accordingly, these compounds areexcellent agents for treatment of many cases demanding myogenic agentand antiestrogenic agent.

They may be utilized for treatment of malnutrition, recovery fromemaciation, convalescence, senility, wasting diseases and disorders ofnutrition, promotion of growth of immature infant, promotion ofgranulation and protein metabolism, increase in body weight, stimulationof appetite, acceleration of recovery from post-surgical condition, andfor treatment of diseases or conditions demanding anabolic agents. Theymay also be utilized for treatment of mastopathy, endometriosis,regulation of conception and many other cases demanding antiestrogenicagents or other cases demanding the pharmacological activity of thesecompounds, in a daily dose of 1 to 500 mg. to human or veterinary orpoultry uses.

The compounds of the present invention are used in human or veterinarymedicine or baits solely or in combination or in preparation of a solidor liquid pharmaceutical excipient. The preparations are prepared byknown methods, for example with the use of pharmaceutical organic orinorganic excipients suitable for enteral or parenteral administration.Suitable excipients are substances that do not react with the compoundsof the present invention such for example as water, vegetable oils,benzyl alcohol, polyethylene glycols, gelatine, lactose, starches,magnesium stearate, talc, white petroleum jelly, isopropyl myristate orother known pharmaceutical excipients. Preparations for parenteraladministration are specially made solutions and, above all, oily oraqueous solutions, furthermore, suspensions, emulsions or implants. Forenteral administration there are similar preparations also containingother therapeutically useful substances. The content of the activecompound in these preparations such, as of an ampoule is preferably 1007to 500 mg., or 100 p.p.m. to 50%, if required in an unit dose.

In order that the invention may be well understood, the followingexamples will be given by way of illustration only, and are not intendedto limit the scope of the present invention. In the following examples,CD means value of molecular rotation of circular dichroism at a wavelength specified at the right foot of Nujol is a trade name of apurified liquid paraffin.

EXAMPLE 1 (A) Into a solution of 7a-methyl-28,3j8-epoxy-5aandrostan-17B-ol (1.098 g.) in 10.0 ml. of tetrahydrofuranis added a solution of thiocyanic acid in ether the latter being,prepared from 7.0 g. of potassium thiocyanate, 6.0 ml. of phosphoricacid, 50 ml. of ether and 2.0 ml. of water. The mixture is allowed tostand over night at room temperature. The reaction mixture is pouredonto icewater and extracted with dichloromethane. The organic layer iswashed with water and aqueous sodium hydrogen carbonate, dried andevaporated. The residue is recrystallized from ether to give 1.222 g. of70c-Il16thYl-3a-thl0- cyanato-Sa-androstane-2fl,17B-diol, M.P. 204206 C.

IR: 1 2355 3310, 2250 cm."

(B) Into a solution of7oc-In6thYl-3ot-thiOCYfil'lti'tO-Saandrostane-25,1719-diol (1.153 g.),prepared by the method described above, in 11 ml. of dioxane is added asolution of 1.3 g. of potassium carbonate in a mixture of 5.5 ml. ofwater and 11 ml. of methanol. The mixture is stirred over night at roomtemperature. The reaction mixture is poured onto ice-water and extractedwith dichloromethane. The organic layer is washed with water, dried andevaporated. Recrystallization from acetone gives 0.734 g. of7a-methyl-2a,3a-epithio-Sa-androstan-175-01, M.P. 140- 143 C. CD: [01-4680.

EXAMPLE 2 Following the procedure of Example 1B, but substituting 7amethyl 3oz thiocyanato 5a androstane 2 8, 17fl-diol with701,17a-dimethyl-3u-thiocyanato-5a-androstane-2B,17 8-diol,7a-methyl-17u-vinyl-3a-thiocyanato-Saandrostane-23,17fl-diol,7u-methyl-17a-ethynyl-3a-thiocyanato-5a-androstane-2B,17B-diol or7a-methyl-25-p-toluenesulfonyloxy-3a-acetylthio-Sa-androstane-17,8 01,there is obtained, 2a,3a-epithio-7a,17a-dimethyl-5a-androstan- 173 ol,20,3a-epithio-7a-methyl-17a-vinyl-5a-androstan- 17 8-01 or2a,3a-epithio-7a-methyl-l7a-ethynyl-5a-androstan-l7 8-ol, respectively.

EXAMPLE, 3

(A) Into a solution 8fi-methyl-2/i,3B-epoxy-5a-androstan-17/3-ol (1.10g.) in 30 ml. of dioxane is added a solution of thiocyanic acid inether, prepared from 7.6 g. of potassium thiocyanate, 13.48 g. ofphosphoric acid, 100 ml. of ether and 10 ml. of water. The mixture isstirred for 1 hour at room temperature. The reaction mixture is pouredonto ice-Water and extracted with dichloromethane. The organic layer iswashed with water and aqueous sodium hydrogen carbonate, dried andevaporated. The residue is recrystallized from methanol to give 1.07 g.of 8B-methyl-3a-thiocyanato-5a-androstane-2;3,l7fl-diol, M.P. 235 C.

(B) Into a solution of 8B-methyl-3a-thiOcyanato-Saandrostane-26,17B-diol(0.50 g.), prepared by the method described above, in 5.0 ml. of dioxaneis added a solution of 0.65 g. of potassium carbonate in a mixture of2.25 ml. of water and 6.0 ml. of methanol. The mixture is stirred for 1hour at room temperature. The reaction mixture is poured onto ice Waterand extracted with dichloromethane. The organic layer is washed withwater, dried and evaporated. Recrystallization from ether gives 0.322 g.of 8,8- methyl-2a,3a-epithio-5a-androstan-17 8-01, M.P. 136 C. CD: [0]-4840.

EXAMPLE 4 EXAMPLE 5 (A) Into a solution of 7u-methyl-2fl,3B-epoxy5ozandrostan-17/3-ol acetate (1.098 g.) in 10 ml. of tetrahydrofuran isadded a solution of thiocyanic acid in ether, prepared from 7.0 g. ofpotassium thiocyanate, 6 ml. of phosphoric acid, 50 ml. of ether and 2ml. of water. The mixture is allowed to stand over night at roomtemperature. The reaction mixture is diluted with chloroform and washedwith aqueous sodium carbonate and water, dried and evaporated.Recrystallization of the residue affords 1.153 g. of7u-methyl-3ot-thiocyanato-5rat-androstane- 2,6,17/3-diol 17-acetate.

IR: my 2269, 1728 cm.-

(B) Into a solution of 7a-methyl-l7fi-acetyloxy-3ot-thiocyanato-5a-androstan-2B-ol (200 mg.) and 5 ml. of dioxane is added asolution of 20 ml. of potassium carbonate in a mixture of 3 ml. of waterand 10 ml. of methanol, and left standing at room temperature overnight. The reaction mixture is poured onto ice water and extracted withdichloromethane. The extract is washed with water, dried and evaporated.Recrystallization of the residue from acetone affords 187 mg. of 20a,3aepithio- 7a-methyl-5a-androstan-17,8-01 acetate, M.P. 159161 C. CD1[012 -3730.

EXAMPLE 6 (A) Into a solution of8B-methyl-ZB,3/3-epoxy-5u-androstan-17B-ol acetate (0.500 g.) in 30 ml.of ether is added a solution of thiocyanic acid in ether, prepared from3.8 g. of potassium thiocyanate, 6.74 g. of phosphoric acid, 50 ml. ofether and 3 ml. of water. The mixture is allowed to stand at roomtemperature overnight. The separated crystals are collected andrecrystallized from ether-petroleum ether to give 0.433 g. of8fl-methyl- 3a-thiocyanato 5a. androstane-25,17B-diol 17-acetate, M.P.143144 C.

IR: 1123;? 2250, 1.730 cm.

(B) methyl 17p acetyloxy-3a-thiocyanato-5aandrostan-Zfi-ol (0.400 g.) in10 ml. of dioxane is added to a solution of 50 mg. of potassiumcarbonate in a mixture of 5 ml. of water and 10 ml. of methanol andstirred for 10 hours at 0 C. The reaction mixture is poured ontoice-water and extracted with dichloromethane. The extract is washed withwater, dried and evaporated to afford 385 mg. of residue, Which ischromatographed over alumina to aiford 0.326 g. of2a,3a-epithio-8/8-methyl5aandrostan-17B-ol acetate, M.P. 145 C. CD: [H3730.

EXAMPLE 7 2u,3a-epithio-7a-methyl-5a-androstan 17,8 01 (200 mg.) in amixture of 2.5 ml. of pyridine and 1.1 ml. of acetic anhydride is keptat room temperature over night 7 and then is poured onto ice-water andextracted with dichloromethane. The extract is washed with hydrochloricacid, sodium carbonate and water, dried over sodium sulfate andevaporated. Recrystallization of the residue from acetone affords 206mg. of 2a,3tx-epithio-7a-methyl-5aandrostane-17fl-ol acetate, M.P.158-160 C.

EXAMPLE 8 2u,3a-epithio-8fi-methyl 5a androstan 175 01 (24.7 mg.) in amixture of 0.5 ml. of acetic anhydride and 0.5 ml. of pyridine is keptover night at room temperature, and then is poured onto ice-Water andextracted with dichloromethane. The extract is washed with hydrochloricacid and water, dried over sodium sulfate and evaporated.Recrystallization from acetone gives 20.3 mg. of2u,3a-epithiO-Sfl-methyI-Sa-androstan 175 ol acetate, M.P. 145 C.

EXAMPLE 9 Into a solution of 2u,3rx epithio 7a methyl-Swan EXAMPLE lInto a solution of 2a,3ot-epithio 8B methyl-a-androstan-17B-ol (200 mg.)in 5 ml. of acetic acid is added a solution of chromium trioxide inacetic acid and left standing for 3 hours at room temperature and thenis poured onto ice water. The resultant solid is collected by filtrationand recrystallized from methanol to atford 183 mg. of201,3a-epithiO-SB-methyl-5ct-androstan-17-one.

EXAMPLE 11 Into a solution of2a,3ot-epithio-8/3-methyl-5a-androstan-17-one (100 mg.) in 5 ml. ofether is added a solution of 50 mg. of methyl lithium in 1 ml. of ether.The solution is stirred at room temperature for hours, and then ispoured onto ice-Water. The ether layer is separated, washed with Water,dried and evaporated. Recrystallization of the residue from acetoneaffords 2a,3a-epithio-8,8, 17a-dimethyl-5a-androstan-175-01.

EXAMPLE 12 Into a solution of 2a,3a-epithio-8B-methy1 5aandrostan-l7-one (300 mg.) in 5 ml. of dioxane is added a solution of300 mg. of 30% lithium acetylide in dioxane. The mixture is stirred atroom temperature for 2 hours, and then is poured onto a dilutedhydrochloric acid in ice-water, and extracted with ether. The organiclayer is washed with Water, dried and extracted with ether.Recrystallization of residue from methanol gives:,3aepithio-S/i-methyl-17a-ethynyl-5a-androstan-175-01.

EXAMPLE 17 2a,3a-epithio-l7a-ethynyl 8,8 methyl 5oz androstan-17fl-ol(100 mg.) in 10 ml. of ethyl acetate is hydrogenated under atmosphericpressure at 'room temperature with Lindlar catalyst. After the reactionis ceased, the catalyst is removed by filtration, evaporated in vacuo togive 95 mg. of residue, Purification of the residue by 8 chromatographyand recrystallization afiords 2a,3a-epithio-17a-viny1-8,B-methyI-Sa-andmstan-17,8-01.

What we claim is: 1. A compound of the formula wherein: X represents anoxygen atom, a ketal group or in which R represents a hydrogen atom, analkyl group containing 1-6 carbon atoms, an alkenyl group containing 1-6carbon atoms or an alkynyl group containing 1-6 carbon atoms and Rrepresents a hydrogen atom, a hyd'rocarbon-carboxylic acyl groupcontaining 1-13 carbon atoms, a cycloalkyl group containing up to 10carbon atoms or a cycloalkyl group substituted by a l-lower alkoxygroup, the total number of carbon atoms being 10 or less, and the ripplemark designates that the methyl is in the 70:, 7,8 or configuration. 2.A compound as in claim 1, wherein the methyl group is in the 7a-positionand X is an oxygen atom.

3. A compound as in claim 1, wherein the methyl group is in the8fi-position and X is an oxygen atom.

4. A compound as in claim 1, wherein the methyl group is in the7u-position and X is R and R each being a hydrogen atom.

5-. A compound as in claim 1, in which the methyl group is in the8l8-position and X is R and R each being a hydrogen atom.

6. A compound as in claim 1, wherein the methyl group is in the7a-position and X is R being a methyl group and R" being a hydrogenatom.

7. A compound as in claim 1, wherein the methyl group is in the8/3-position and X is R being a methyl group and R being a hydrogenatom. 8. compound as In claim 1, wherein the methyl group is in the7a-position and X is R being a vinyl group and R being a hydrogen atom.9. compound as in claim 1, wherein the methyl group is in theSir-position and X is 9 10 R being a vinyl group and R" being a hydrogenatom. 13. A compound as in claim 1, wherein X is 10. A compound as inclaim 1, wherein the methyl group is in the 7a-positi0n and X is OR B! 5R" being a l-lower-alkoxycycloalkyl group.

14. A compound as in claim 13, wherein R" is a 1- R being an ethynylgroup and R" being a hydrogen lower-alkoxycyclopentyl group.

atom. 15. A compound as in claim 13, wherein R" is a 1- 11. A compoundas in claim 1, wherein the methyl lower-alkoxycyclohexyl group. group isin the 8,B-position and X is 10 16. A pharmaceutical composition whichcomprises a pharmaceutically elfective amount of a compound of claim 1in admixture with a pharmaceutical carrier.

1 References Cited 0 UNITED STATES PATENTS R being an ethynyl group andR" being a hydrogen 3,301,850 1/ 1967 Klimstra 260-2395 atom. 3,405,12410/ 1968 Klimstra 260239.5 12. A compound as in claim 1, whereln X is3,341,523 9/1967 Komeno 260239.5 20 3,422,192 1/1969 Komeno 260239.5ORII ELBERT L. ROBERTS, Primary Examiner R US. 01. x11.

602 .5, 2 9.5 R being a lower hydrocarboncarboxylic acyl group. 25 2 393 5

